Pyrazolothiazepines and isoxazolothiazepines

ABSTRACT

7,8-Dihydro-4-oxopyrazolo(3,4-d) (1,3)thiazepines which may be substituted in the 1-, 3-, 5-, 7- and/or 8- position and the corresponding isoxazolo(5,4-d) (1,3)thiazepines which may be substituted in the 3-, 5-, 7- and/or 8- position are prepared by converting a 5-aminopyrazole which may be substituted in the 1and/or 3-positions or a 5-aminoisoxazole which may be substituted in the 3-position into a Schiff base and subsequent condensation of the Schiff base with thioglycolic acid or a substituted thioglycolic acid. The new compounds are useful antiinflammatories.

United States Patent Swett et al. 5] June 13, 1972 [54] PYRAZOLOTHIAZEPINES AND [5 R f r ces Cited ISOXAZOLOTHIAZEPINES OTHER PUBLICATIONS [72] Inventors: Leo Ralph Swett; James Daniel Ratajczyk, Surrey-J. Am. Chem. Soc. 69, 291 l- 2912 1947) both of Waukegan, Ill.

Primary Examiner-Alex Maze] [73] Assignee. Abbott Laboratories, North Chicago, Ill. Asst-Slam Examiner R v Rush 2 1 Filed; Aug 20 1970 Attorney-Robert L. Niblack [21] Appl. No.: 65,698 [57] ABSTRACT Related s, Application Data 7,8-Dihydro-4-oxopyrazolo[3,4-d] 1,3]thiazepines which may be substituted in the l-, 3-, 5-, 7- and/or 8- position and commuatlon'm'pan of 3611 750,430, g- 1, the corresponding isoxazolo[5,4-d] [l,3]thiazepines which 1968,aband0ned. may be substituted in the 3-, 5-, 7- and/or 8- position are prepared by converting a S-aminopyrazole which may be sub- [52] U.S.Cl ..260/307 H, 260/293.87, 260/310R, stituted in the land/or 3-p0sitions or a S-aminoisoxazole 424/263, 424/272, 424/273 which may be substituted in the 3-position into a Schiff base 51 Int. Cl. ..C07d85/22 and Subsequent Condensation of the Schiff base with g w Search 6()/3()7H 3 0 thiogiycolic acid or a substituted thioglycolic acid. The new compounds are useful anti-inflammatories.

11 Claims, No Drawings PYRAZOLOTHIAZEPINES AND ISOXAZOLOTHIAZEPINES RELATIONSHIP OF OTHER APPLICATIONS This application is a continuation-in-part of our previous application Ser. No. 750,430, filed on Aug. 1, 1968, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a new process for making compounds of heretofore unknown ring systems; more particularly, this invention is concerned with the preparation of compounds of the formula R4 (I? R4 i l-CH C-Cfi R| R S S It M1... N x t l...

l RfR R n R V (1) wherein R is hydrogen, loweralkyl or phenyl, R is hydrogen, loweralkyl, phenyl or cyclohexyl, R is loweralkyl, cyclopropyl, 2-furyl or wherein X is hydrogen, halogen, trifluoromethyl, hydroxy, loweralkoxy or dimethylamino and Y is hydrogen, chlorine or loweralkoxy, R is hydrogen or loweralkyl, R is hydrogen loweralkyl or carboxyloweralkyl and R is hydrogen, loweralkyl or diloweralkylaminoloweralkyl. In all instances, the term loweralkyl or loweralkoxy is intended to refer to saturated hydrocarbon chains of 1-7 carbon atoms. The new compounds are useful anti-inflammatories, producing a marked reduction of edema when orally administered to wannblooded animals at a dosage of between 5 and 100 mg./kg. The compounds wherein R and/or R is hydrogen can also be used as the precursors for compounds of the formula ll T N l in it wherein R, R R R" and R have the above-defined meaning.

These pyrazolopyridinones have also been found to have excellent anti-inflammatory activity in warm-blooded animals.

In a general embodiment of the new process, a Schiff base of the formula C OOH (IV) wherein R has the meaning defined above, in the presence of an inert solvent boiling above 50 C. at a temperature between 60 and 150 C. for a period of between 30 minutes and several hours and recovering the formed isoxazoloor pyrazolothiazepinone from the reaction mixture. The compounds wherein R is different from hydrogen are made from the compounds wherein R is hydrogen by well-known procedures. The term inert" used in defining the reaction medium for the above condensation is meant to express that the solvent does not react with either starting material or the formed condensation product. Where the solvent used in the condensation reaction described above is water-immiscible, it is preferred to use a reaction vessel permitting the continuous removal of water during the reaction; when the inert solvent used as the reaction medium is water-miscible, the condensation product can easily be isolated by partial evaporation of said solvent and crystallization of the condensation product. Suitable reaction solvents are aromatic hydrocarbons like benzene, xylene, etc. and alcohols such as ethanol, butanol, etc.

In a minor modification of the above outlined general procedure for making the new compounds of formula I, the correspondingly substituted 5-aminopyrazole or isoxazole is reacted with an aldehyde of formula RCI-l O or a ketone of the formula R R C O in an inert solvent by a standard procedure for making the desired Schiff base; the selected thioglycolic acid of formula IV is subsequently added to this reaction mixture (without isolating the Schiff base) for the condensation leading to the desired isoxazoloor pyrazolothiazepinone. The condensation reaction is usually complete in about 3 hours but often a heating period of 30 minutes is sufficient. Thus, the process can easily be adapted for continuous operation.

The formation of the isoxazoloor pyrazolothiazepinones by the present process is not only novel but surprising as well since ordinarily one would expect this condensation to produce a thiazolidone in accordance with the reaction described by Surrey (J. Am. Chem. Soc., 69, 2911 of 1947).

In order to illustrate specific embodiments of the present process, the following examples are given here. These examples are to be understood only to show the preparation of specific compounds of the new series and are not meant to limit the invention in any respect.

EXAMPLE I a. 23.5 g. of l,3-diphenyl-S-aminopyrazole and 10.6 g. of benzaldehyde in 50 ml. of ethanol are refluxed for three hours. The reaction mixture is then allowed to cool and solidify. The crude product is filtered, washed with ethanol and recrystallized from ethanol to yield 25.2 g. of 5-(benzylideneamino)- 1,3-diphenylpyrazo1e, melting at 112 -1 14 C. The infrared spectrum is compatible with the assigned structure and microanalysis shows excellent agreement with the calculated values for the compound of empirical formula c n u In a condensation apparatus equipped with a water separator, 3.23 g. of the above described Schiff base and 1.1 g. of thioglycolic are placed in 50 ml. of benzene and refluxed for 5 hours after which time the solvent is removed under vacuo. The residue is taken up in ether and hexane is added to this solution until it becomes turbid. The mixture is allowed to stand over night, producing a precipitate weighing 1.3 g. and melting at l82-193 C. This precipitate is recrystallized from benzene/hexane in the above fashion to produce pure 7,8- dihydrol ,3,7-triphenyll H-pyrazolo[3,4-d] 1,3] thiazepin- 4(5I-l)-one H)-one, melting at l97-199 C.

b. When in the above example 44 g. of the Schiff base is condensed with 17.8 g. of thioglycolic acid in ml. of toluene by refluxing the mixture for 3 hours and concentrating the volume thereafter to about one third, the addition of ether precipitates 35 g. (65 percent of theory) of the above pyrazolothiazepinone.

EXAMPLE 2 By using the procedure described in Example 1b, the condensation of 19.9 g. of 5-(benzylideneamino)-l,3-dimethylpyrazole and 9.2 g. of thioglycolic acid in 75 ml. of toluene,

16.8 g. of 7,8-dihydrol ,3-dimethyl-7-phenyl-1H- pyrazolo[ 3,4-d] l ,31thiazepin-4(5l-l)-one, melting at 205-207 C is obtained.

EXAMPLE 3 By following the procedure of Example lb using 16.2 g. of -(benzylideneamino)-l,3-diphenylpyrazole and 5.9 g. of mercaptosuccinic acid in 150 ml. of toluene, a clear solution forms after about 30 minutes of refluxing. Upon continued refluxing, a precipitate starts to form. After another 60 minutes, the mixture is cooled and the toluene is decanted. leaving a yellow, sticky mass. After triturating this mass with ethanol, filtration and recrystallization from dimethyl-formamide/water, 3.6 g. of 5-carboxymethyi-7,8-dihydro-l,3,7- triphenyllH-pyrazolo[ 3 ,4-d l ,3 ]thiazepine-4( S )H-one, melting at 253-255 C is obtained.

EXAMPLE 4 By substituting the Schiff base of Example 1 with the corresponding 5-( 4-chlorobenzylideneamino)- l ,3-dimethylpyrazole, condensation under reflux in toluene with water separation for 5 hours produces 7-(4-chlorophenyl)-7,8- dihydro-l ,3-dimethyll H-pyrazolo[ 3 ,4-d 1 ,31thiazepin-4 (5H)-one in a yield of 63 percent. The pure compound melts at 204-206 C.

By using the corresponding 4-fluoro compound, the analogous 7-(4-fluorophenyl) derivative is obtained. The activity of this compound is established by the following procedure: edema is produced in the paws of rats by the injection of carrageenan according to the method described by Winter et al. (Proc. Soc. Exp. Bioc. Med. 1962, volume 1 l l page 544). The above compound is administered orally at various dosages (six rats per dosage) 30 minutes prior to the administration of the edema producing carrigeenan. Edema is inhibition is calculated from the difference between the average edema size of a control group of animals and the average edema size of each test group. The ED (i.e., the dose required to produce 25 percent edema size reduction) is determined from a dosage/effect curve drawn on logarithmic graph paper and is established at 25 mg./kg. for the above fluoro-compound; with 10 and 50 mg./kg., respectively, an edema reduction of 16 percent and 61 percent is obtained.

For the above chloro-compound, the experimentally caused edema are reduced by 20 percent after oral administration of mg./kg. and 49 percent with 50 mg./kg.

EXAMPLE 5 By substituting the Schitf base used in Example 4 with 5- (3,4-dichlorobenzylideneamino)- l ,3-dimethylpryrazole, an equally good yield of 7-(3,4-dichlorophenyl)-l,3-dimethy|- 7,8-dihydro-lH-pyrazolo[3,4-d] [l,3]thiazepin-4(5H)-one is obtained. Upon oral administration of this compound to rats by the method shown in Example 4, edema reduction by 38 percent and 61 percent are found with 10 mg./kg. and 25 mg./kg., respectively.

EXAMPLES 6-30 In the following examples, the procedure of Example 1(b) is repeated using the Schiff bases of above formula III with R, R, R and R as identified in the following table, a thioglycolic acid of formula IV with R as identified below and the indicated solvent. The compounds so prepared are identified below with their melting point and their chemical name in which the Z is used as the abbreviation for 7,8-

expressed aspercent increase over normal paw size; Edema 35 dihydr II I- yra IQBA-d] {l,3]thiazepin-4(5H)-one.

ski. ,4 l 5 l HSCHRCO OH Resulting compound Ex. M.p. N o. R R R R R Solvent C: Name 6 0 H3 CH; Cl 11 II Toluene 2802 7- (2,4-diehl0rophenyl)1,3-dimethyl-Z.

7 C l I 1; C II 3 ll C H: C O O H .do 240-2 5-carboxymethy1-7-(4-ehlorophenyl) l ,3-

(,1 dimethyl-Z.

8 CIIJ CH: F I I II .do l979 1,3-dirnethyl-7-(4-fiuorophenyD-Z.

9 0 ll; C II; C F: l I ll .do HIS-6 l ,3-tlimetl13 l-7-(4-tiifluoromethylphenyU-Z.

10 Cl I3 C II; IN) (I) Cl I; ll ll .do 210-21" l,3-dimethy1-7-(Z-hydroxy-S-muthoxyphenyD-Z.

11 CH CH3 CH3? (|)CII II II .do 170-2 7-(2,3-dimethoxyphenyl)-l,3-dimethyl-Z.

1'2 C II; CH 01 II CH3 .do 2101 7-(4-chlorophenyl)1,3,5-trimethyl-Z.

l3 CH3 CH1 F CH H do 206-8 7-(4-fiuorophenyl)1,3,7-trimethyl-Z.

14 C H: CH3 I I I H .do 215-7 1,3-dimethyl-7-(4-iodophenyD-Z.

15 Ph OH; Q01 H II .do.. 212-14 7- (-chlorophenyl) -1-methy1-3-pl1enyl-Z.

16 CH1 CH1; @011 H H do 268-70 1,3-dimethYlJ-(4-hYdr0XYDhenYl)Z.

l7 C Ha C H3 H H H do 7 1,3-dimethyl-7-(2-iuryl)-Z.

l8 0 H3 H do 2802 7-(kehlorophenyl)-3-metl1yl-Z.

a II II Schifi Base HSCHR COOH Resulting compound M.p., 1 12. R R R R R Solvent 0. Name 19 CH3 CH3 5 Cl Oil; 11 .do.. 248-60" 7-(4-chlorophonyl)-1,3,7-trimethyl-z.

CH3 CH3 (Ill; CH II d0 USS-90 1,3,7,7-tetramethyl-Z. 21... CH; 3-MeBu @F H II do. ISO-2 3-methyl-1-(3-rnethylbutyl)-7-(4rfluoropheny1)-Z. 22 CH3 CH3 NM II II do 206-9" 1,3-dlmethyl-7-(-dimethylaminophenyl)-Z.

23.. (illil (31h lr ll ll do..... 1l8-15 1,3-dimetl1yl-7-propyl-Z. .14 (.Hu (.1 1;. A (Ill: ll 'llonzeuo. 161-8" 7-cyclopropyl-l,3, 7-trinwthyl-i6.

25.. (ill; Ulla 1 ll. ll 'lolueno... 204-6 7-(4-bromophonyD-l,B-dlmotlryl-Z.

26. ll lh Q 01 H H do. 16971 7-(4-chlorophenyD-1-phenyl-Z. 27. H Ph Q F H H .do 191-193" 7-(4-fiuorophenyl)-1-phenyl-Z. 28""... H @F H H ...do.. 1703 1-cyclohexyl-7-(4-fluorophenyl)-Z. 29 H CH3 H H ..do. 121-3 7-( l-fluorophenyl)-1-methyl-Z.

30 H CH3 CH3 CH3 H d0.. 205.57 1,7, 7-trimethyl-Z.

In all of the above examples, except No. 6, the procedure of 4 After 'firirion subsides, the mixture is filtered and the Example 1(b) is used without isolation of the intermediate Schiff base. The solvent indicated above is used to condense the pyrazole with the aldehyde or ketone and after refluxing the mixture for at least two hours, the thioglycolic acid is added for the final condensation reaction. In Example 6, the intermediate Schiff base is prepared according to Example 1(a).

In the following examples, compounds of formula I wherein R is different from hydrogen are made from compounds described in previous examples.

EXAMPLE 31 To a solution of 5.82 g. of the compound of Example 8 in 50 ml. of water containing 0.8 g. of sodium hydroxide, 2.52 g. of dimethylsulfate is added. After the initial foaming subsides, an oil separates. An additional amount of 0.5 g. dimethylsulfate is added and the mixture is stirred two hours at room temperature. The oil is separated by adding chloroform and removal of the aqueous phase. The chloroform solution is washed with water and dried. The solvent is removed by vacuum distillation. The oil solidifies; it is triturated with ether and the solid is separated by filtration, leaving 2.6 g. of crude 1,3,8-trimethyl- 7-( 4-fluorophenyl)-7,8-dihydrol l-i-pyrazolo[ 3,4-d][ l,3]thiazepin-4( 5l-l)-one. The pure compound, recrystallized from dimethylformamide/water, melts at l25-7.

EXAMPLE 32 In the manner described in Example 31, the compound of Example 5 is converted to l,3,8-trimethyl-7-( 3,4- dichlorophenyl )-7,8-dihydrolH-pyrazolo[ 3,4-d][ l.,3]thiazepin-4( 5l-l)-one, melting at l65.7. A yield of 76 percent of theory is observed.

EXAMPLE 33 A mixture of 5 .82 g. of the pyrazolothiazepinone of Exam- 7 mixture is stirred for three hours at C. and water is then added cautiously to destroy any excess of sodium hydride.

residue is dried in vacuum. The oily residue is placed in a mixture of chloroform and water. The chloroform layer is washed with water and then extracted with dilute hydrochloric acid solution. Again, the chloroform layer is separated, then dried and concentrated. The residue solidifies and is identified as unreacted starting material. The acid fraction is made basic by adding a 50 percent aqueous sodium hydroxide solution which is then extracted with chloroform. The chloroform layer is separated, washed with water, dried and concentrated to produce an oil. The oil is dissolved in ether and ethereal hydrochloric acid is added, producing 4.2 g. of a residue melting at l93-7 C with decomposition. After crystallization from ethanol/ether, 2.2 g. of pure 1,3-dirnethyl-8-(2- dimethylaminoethyl )-7-( 4-fluorophenyl )-7 ,8-dihydro- 1H- pyrazolo[ 3 ,4-d] [l,3 ]thiazepin-4( 5H)-one dihydrochloride melting at 238-40 C is obtained.

This hydrochloric acid salt is dissolved in water and made alkaline by adding a 10 percent aqueous sodium hydroxide solution. The solid obtained is filtered, washed with water, dried and crystallized from hexane yielding the free base of the above compound having a melting point of l l0-l2 C and showing analytical values in good agreement with those calcu- EXAMPLE 34 A mixture of 14,7 g. 3-methyl-5-aminoisoxazole, 21.1 g. of 4-chlorobenzaldehyde and 200 ml. of toluene are refluxed in an apparatus equipped with a water separator. After three hours, the mixture is cooled and 13.85 g. of thioglycolic acid is added. Refiuxing is continued for another two hours and subsequently, toluene is driven off to reduce the volume to about 180 ml. Upon cooling, a dark brown oil separates. The toluene solution is decanted and the oil triturated with an equal volume of ether, cooled over night, and decanted again. The toluene-ether mixture is evaporated to dryness, leaving 37.3 g. of a clear, hard, light orange residue. Several recrystallizations of this product from ethanol produces pure 7-(4-chlorophenyl)-7,8-dihydro-3-methylisoxazolo[ 5,4-d][ l ,3 ]-thiazepin-4( 5 H)-one, melting at 2 l 8-20 C. Edema in rats is reduced by 44 percent upon administration of 25 mg./kg. of this compound.

EXAMPLE 35 A mixture of g. of 3-methyl-5-aminoisoxazole and 26.5 g. of benzaldehyde is refluxed for three hours in 50 ml. of ethanol. The solvent is then evaporated and the crude residue 5 is refluxed for 3 hours with 23 g. of thioglycolic acid in 100 ml. of toluene, using a water separator. Subsequently, hot hexane is added and the mixture is then allowed to stand for several days during which time the oil initially separating starts to crystallize. The solvent mixture is decanted and ethanol is added. Upon stirring, the remaining oil crystallizes. The crystals are filtered off, washed with ether and recrystallized from 500 ml. ethanol to produce pure 3-methyl-7,8-dlihydro-7 phenylisoxazolo[ 5,4-d][ l ,3 ]thiazepin-4( 5H )-one, melting at 2 l 6-l 8bL C.

EXAMPLE 3 6 Using an equivalent amount of 3,4-dichlorobenzaldehyde in place of the 4-chlorobenzaldehyde used in Example 34, 3 7- 3 ,4-dichlorophenyl )-7 ,8-dihydro- 3-methylisoxazolo[ 5 ,4-d [l,3]thiazepin-4(5l-l)-one, melting at 2459 C (recrystallized from dimethylformamide/water) is obtained. Upon oral administration of 50 mgJkg. of this compound to rats, their edema size is reduced by 28 percent.

EXAMPLE 3 8 In a repetition of Example 34 but using 4- chloroacetophenone for making the Schiff base, 7-(4- chlorophenyl)-7 ,8-dihydro-3 ,7-dimethylisoxazolo[ 5,4-d l ,3 ]thiazepin-4( 5l-l) one is obtained. The product melts, after several recrystallizations from dimethylformamide/water, at 280-95bL with decomposition.

EXAMPLE 39 In the fashion of the above examples but using acetone for making the Schiff base 5-isopropylidineamino-3-methylisoxazole, 7,8-dihydro-3,7,7-trimethylisoxazolo-[5,4-d]-[ l,3]thiazepin-4(5l-l )-one melting at 197.5 8.5 C is obtained. This compound reduces the size of an edema by 8 percent when administered orally at a dose of mgJkg. to rats. 50

EXAMPLE 40 To a solution of 2.95 g. of the compound prepared in Example 34 in 25 ml. of 20 percent aqueous sodium hydroxide, a few drops of 50 percent aqueous sodium hydroxide is added to make the solution strongly alkaline. Dimethylsulfate (1.26 g.) is then added at once: within less than a minute, a crystalline solid separates from the stirred solution. After two hours stirring at room temperature, the hard crystals are filtered off, washed with water and dried in air, yielding l.7 g. of crude 7- (4-chlorophenyl)-7,8-dihydro3,8-dimethylisoxazolo[5,4- d]]l,3]-thiazepin-4(5H)-one. This product is recrystallized from ethanol/water; it melts at 102-6 C and is obtained in long, white needles. Oral administration of 50 mg./kg. of this compound to rats with edema produces a 12 percent edema size reduction.

As mentioned, substituting the free hydrogen in the 8-position of the compounds of formula I can be accomplished by known and standard methods as exemplified above. However, the molar ration between the pyrazolothiazepinone and the alkylating agent should not exceed the proportion l:l because, when the alkylating reagents used exceed the equimolar proportion, an entirely different ring structure is obtained. For instance, by carrying out the procedure of Example 33 with the starting material described in Example 5 but using two molar equivalents of sodium hydride and two molar equivalents of methyl iodide, 6-(3,4-dichlorophenyl)-l,3,7-trimethyl-4H- pyrazolo-[3,4-b1pyridin-4-one is obtained; it melts at 200-20 2 C. after crystallization from dimethylformamide/water. As mentioned above, this compound is also useful as an anti-inflammatory for warm-blooded animals: an oral dose of 85 mg./kg. reduces edema size by 25 percent.

In similar manner, the free base of Example 8 converts to 6- (4-fluorophenyl)- l ,7-dihydro-l ,3,7-trimethyl-4H-pyrazolo[ 3,4-b][ 1,3 )pyridin-4-one 2 molar equivalents of sodium hydride and methyl iodide are used. This compound melts at l857 C. and when applied orally at a dose of 56 mg./kg. to rats, an edema size reduction of 25 percent is observed.

The new pyrazolothiazepinones described above are thus useful in the field of anti-inflammatories in two ways: they can be used directly, or they may be used as the starting materials for making other valuable anti-inflammatory compounds by the described ring contraction process. The described isoxazoloand pyrazolothiazepines of formula I both produce significant edema reduction when orally administered in dosages between 5 and lOO mg./kg. These dosages are extremely small when considered in view of their toxicities: in most instances, the oral LD is well above 500 mg./kg. and often l,000 mg./kg. which reflects the excellent therapeutic index of these compounds. An excellent therapeutic index is also apparent for the compounds with the pyrazolopyridinone structure made from the above pyrazolothiazepines: their oral LD values are mostly 1 ,000 mgJkg.

In biologically evaluating the compounds of the new series, another very interesting observation was made; the compounds described in Examples 4, 5, 8, 14, 25, 34 and 37 possess pronounced anti-depressant activity. For instance, the compound of Example 4 produces a 3+rating on a 0-3 activity scale in the modified DOPA test described by G. Everett in Proceedings of the First lntemational Symposium on Antidepressant Drugs" (published by Excerpta Medica Foundation, Amsterdam; February 1967, page 164) when administered orally at a dose of 25 mg./kg. to rats, while showing no monoamineoxidase inhibition at doses between 25 and 200 mg./kg. The combination of stimulant (anti-depressant) and anti-inflammatory activity is of great value, particularly in the field of veterinary medicine.

The compounds described in Example 4, 5, 8, 14, 25, 34 and 37 of this invention have also been found to enhance performance when administered orally to slow learners in dosages of from 10 to mg./kg. of body weight daily. The compounds facilitate the acquisition of conditioned avoidance behavior and the retention of learning in rats following electroconvulsive shock in the Sidman shock avoidance procedure.

The new compounds of formula I can be effectively administered orally and some representatives also are effective through other routes of administration, e.g., through injections or topical. For oral administration, the compounds may be suspended or dissolved in a pharmaceutically acceptable medium or they can be combined with a pharmaceutically acceptable solid carrier for the preparation of pills, capsules or tablets. For either the liquid or solid dosage form, the free base of the above compounds as well as their non-toxic acid addition salts may be used. The preferred salts for this purpose are the hydrochloride, the sulfate, the citrate, the phosphate or the acetate. These salts may be used alone or combinations of salts may be used to produce specific effects; for instance, a readily absorbable salt and a slowly dissolving salt may be combined into a combination product giving fast and longlasting effects, respectively. The salts, of course, may be based on different compounds of formula I or the free base of one compound may be combined with a salt of another representative of this new class of compounds.

We claim:

1. The process of preparing an isoxazolo[5,4-d][ 1,3]- or a pyrazolo [3,4-d] [1,3 ]thiazepinone of the formula wherein W is or NR and wherein R is hydrogen, loweralkyl or phonyl, R is hydrogen, loweralkyl, phenyl or cyclohexyl, R is loweralkyl, cyclopropyl, 2-furyl or wherein X is hydrogen, halogen, trifluoromethylfliyziroxy,

loweralkoxy or dimethylamino and Y is hydrogen, chlorine or loweralkoxy, R is hydrogen or loweralkyl, R is hydrogen, loweralkyl or carboxyloweralkyl and R is hydrogen, consisting essentially in condensing a Schiff base of the formula with a carbonyl compound of the formula R R CO, in an inert solvent selected from the group consisting of ethanol, benzene and toluene.

5. A pyrazolo[3,4-d] [1,3 ]thiazepinone or an isoxazolo [5,4-d] 1,3]thiazepinone of the formula wherein W is 0 or NR R is hydrogen, loweratlkyl or phenyl, R is hydrogen, lowemlkyl, phenyl or cyclohexyl, R is loweralkyl, cyclopropyl, Z-furyl or wherein X is hydrogen, halogen, trifluoromethyl, hydroxy, loweralkoxy or dimethylamino and Y is hydrogen, chlorine or loweralkoxy, R is hydrogen or loweralkyl, R is hydrogen, loweralkyl or carboxyloweralkyl and R is hydrogen, loweralkyl or diloweralkylaminoloweralkyl.

6. The compound of claim 5 wherein Wis NR R and R are methyl, R is 4-chlorophenyl and R, R and R are hydrogen.

7. The compound of claim 5 wherein R and R are methyl, R is 4-fluorophenyl, and R, R and Rare hydrogen. 5

8. The compound of claim 5 wherein Wis NR R and R are methyl, R is 3,4-dichlorophenyl and RR and R are hydrogen.

9. The compound of claim 5 wherein Wis 0 R is methyl, R is 4-chlorophenyl and R, R and R are hydrogen.

10. The compound of claim 5 wherein Wis O R is methyl, R is 3,4-dichlorophenyl and R", R and R are hydrogen.

11. The compound of claim 5 wherein Wis NR R and R are methyl, R is 4-iodophenyl and R, R and R are hydrogen.

Disclaimer 3,669,983.Leo Ralph Swett and James Dam'el Ratajeeg lc, Waukegan,

I11. PYRAZOLOTHIAZEPINES AND ISOXAZOLOTHIAZE- PINES. Patent dated June 13, 1972. Disclaimer filed May 2, 1974:, by the assignec, Abbott Laboratories.

Hereby enters this disclaimer to claims 1-11 inclusive of said patent.

[Oyfiez'al Gazette December 524, 1974.] 

2. The process of claim 1 wherein said inert solvent is ethanol.
 3. The process of claim 1 wherein said inert solvent is toluene.
 4. The process of claim 1 wherein said Schiff base is formed in situ by condensing an aminopyrazole or an aminoisoxazole of the formula with a carbonyl compound of the formula R2R3CO, in an inert solvent selected from the group consisting of ethanol, benzene and toluene.
 5. A pyrazolo(3,4-d) (1,3)thiazepinone or an isoxazolo (5,4-d) (1,3)thiazepinone of the formula
 6. The compound of claim 5 wherein R and R1 are methyl, R2 is 4-chlorophenyl and R3, R4 and R5 are hydrogen.
 7. The compound of claim 5 wherein R and R1 are methyl, R2 is 4-fluorophenyl, and R3, R4 and R5are hydrogen. 5
 8. The compound of claim 5 wherein R and R1 are methyl, R2 is 3,4-dichlorophenyl and R3R4 and R5 are hydrogen.
 9. The compound of claim 5 wherein R is methyl, R2 is 4-chlorophenyl and R3, R4 and R5 are hydrogen.
 10. The compound of claim 5 wherein R is methyl, R2 is 3,4-dichlorophenyl and R3, R4 and R5 are hydrogen.
 11. The compound of claim 5 wherEin R and R1 are methyl, R2 is 4-iodophenyl and R3, R4 and R5 are hydrogen. 